Process for preparation of S-(-)-betaxolol and salts thereof

Abstract

The present invention relates to an improved process for preparation of S-(−)-betaxolol salts. More particularly the present invention relates to the preparation of hydrochloride salt of S-(−)-betaxolol of formula (1)

1. A process for the preparation of S-(−)-betaxolol of the formula (3) and hydrochloride or maleate salt of the formula (1) which comprises                  
 a. selectively benzylating 2-[4-hydroxyphenyl-ethanol] with benzyl halide in the presence of base and an organic solvent to obtain 2-[4-benzyloxyphenyl-ethanol]; 
 b. condensing 2-[4-benzyloxyphenyl-ethanol] with an allyl halide in the presence of a base and an organic solvent to obtain 1-(2-allyloxyethyl)-4-benzyloxybenzene; 
 c. cyclopropanating 1-(2-allyloxyethyl)-4-benzyloxybenzene to obtain the 1-benzyloxy-4-(2-cyclopropyl methoxy-ethyl)-benzene; 
 d. deprotecting 1-benzyloxy-4-(2-cyclopropylmethoxy-ethyl)-benzene by hydrogenation to obtain 4-(2-cyclopropylmethoxyethyl)-phenol; 
 e. O-Alkylating the 4-(2-cyclopropylmethoxyethyl)-phenol to S(−)-betaxolol by treating with R-(−)-epichlorohydrin in the presence of alkali to obtain a mixture of compounds and treating the mixture with isopropylamine to give S-(−)-betaxolol of formula 3, and if desired 
 f. treating S-(−)-betaxolol with alcoholic hydrochloric acid in organic solvent to give S-(−)-betaxolol HCl, or maleic acid in organic solvent to give S-(−)-betaxolol maleate salt. 
 
     
     
       2. A process as claimed in  claim 1  wherein the base used in step (a) is an alkali metal carbonate selected from the group consisting of carbonates of sodium and potassium. 
     
     
       3. A process as claimed in  claim 1  wherein the base used in step (a) is an alkali hydroxide selected from the group consisting of hydroxides of sodium and potassium. 
     
     
       4. A process as claimed in  claim 1  wherein organic solvent in step (a) is an aliphatic ketone selected from the group consisting of acetone, methyl ethyl ketone and methyl isobutyl ketone. 
     
     
       5. A process as claimed in  claim 1  wherein organic solvent in step (a) is a cyclic ether. 
     
     
       6. A process as claimed in  claim 1  wherein allyl halide used in step (b) is selected from a chloride and a bromide, the base used is selected from sodium hydride and potassium t-butoxide and the solvent used is an ethereal solvent selected from the group consisting of tetrahydrofuran and a polar solvent selected in turn from the group consisting of DMSO, DMF. 
     
     
       7. A process as claimed in  claim 1  wherein cyclopropanation in step (c) is carried out with diiodomethane by Zn—Cu couple (Simmons Smith) or diethyl zinc in hexane Furukawa). 
     
     
       8. A process as claimed in  claim 1  wherein deprotection by hydrogenation in step (d) is carried out using Raney Nickel or by Pd—C. 
     
     
       9. A process as claimed in  claim 1  wherein the alkali used in step (e) is an alkali hydroxide selected from sodium hydroxide and potassium hydroxide. 
     
     
       10. A process as claimed in  claim 1  wherein the solvent used for formation of hydrochloride salt of S(−)Betaxolol is a hydrocarbon selected from the group consisting of toluene, cyclohexane and ethers selected in turn from the group consisting of diisopropyl ether and diethyl ether.